radioimmunotherapy with lu-177 labeled 6a10 fab-fragments in patients with glioblastoma after standard treatment

Conditions: Glioblastom WHO Grade 4

Summary: locoregional, intracavitary radioimmunotherapy (irit) with a newly developed radioimmunoconjugate (lu-177 labeled 6a10-fab-fragments) will be used to prevent or postpone tumour recurrence in patients with gbm following standard therapy . following study objectives will be analyzed: * determining the maximum tolerated dose (mtd) * determining safety by assessing all new neurological, hematological and other aes ctc grade 2 or higher * determining absorbed dose to the 2 cm shell of the resection cavity (based on a series of spect/cts of the head 2h,24h,48h, 72h p.i. and on day 5-7) * determining absorbed dose values for the kidneys, the liver, the active marrow (based on a series of spect/cts of the abdomen 2h,24h,48h, 72h p.i. and on day 5-7) * determining 24 weeks progression-free-survival (pfs), defined from the day of inclusion

in glioblastoma (gbm), tumour recurrence occurs adjacent to the initial tumor resection cavity in about 85% of cases (albert et al., 1994; bashir et al., 1988; nestler et al., 2015). therefore, local treatment concepts seem crucial for effective recurrence treatment strategies. we consider locoregional, intracavitary radioimmunotherapy (irit) to be a new therapeutic approach to delay or prevent the development of local tumour regrowth in gbm patients. by applying a radioimmunoconjugate (ric) into the surgically created resection cavity (rc) the blood-brain barrier can effectively be by-passed, allowing the a deposit of high radiation doses locally while sparing sensitive organs like the bone marrow and the kidneys. lucafab (lu-177 labeled 6a10- fab-fragment) is a carbonic anhydrase xii-specific antibody fab fragment developed by helmholtz munich, labeled with itm's highly pure medical radioisotope, lutetium-177. (itm isotopetechnologies munich se). patients with gbm after standard therapy (surgery by radio-chemotherapy concomitant and adjuvant chemotherapy) are eligible for the study. patients will receive the calculated total doses of lu-177-labeled 6a10-fabs in three fractions with an interval of 4 weeks between injections, administered into the tumour cavity via an implanted reservoir. a patient specific dosing strategy will be applied and will depend on the individual rc volume. this investigator-initiated trial is sponsored by the university hospital münster, conducted in hospitals in münster, essen, cologne, and wuerzburg, and supported by itm and helmholtz munich.

Eligibility criteria:
inclusion criteria: * written patient consent after comprehensive information * age between 18 and 80 years * primary supratentorial high grade glioma after standard therapy (fluorescence-guided surgery, radio-chemotherapy, concomitant + adjuvant chemotherapy), with no or stable small tumor residue (residual contrast enhancement of up to 5cm3) at earliest 6 weeks after completion of radiotherapy * histological verification of glioblastoma and ca 12-expression of tumor cells confirmed * karnofsky-score ≥ 60 * volume of resection cavity 2,5-25 cm3 * male and female patients with reproductive potential must use an approved contraceptive method * pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained prior to treatment start * adequate bone marrow reserve: white blood cell (wbc) count ≥3000/μl, granulocyte count \>1500/μl, platelets ≥100000/μl, hemoglobin ≥ 10 g/dl * adequate liver function: bilirubin \< 1.5 times above upper limit of normal range (uln), alanine transaminase (alt/sgpt) and aspartate transaminase (ast/sgot) \< 3 times uln. in the case of documented or suspected gilbert's disease bilirubin \< 3 times uln. * blood clotting: inr (=pt) and ptt within acceptable limits according to the investigator * adequate renal function: creatinine \ (or equal) 60 ml/min exclusion criteria: * patient unable to undergo imaging by ct, pet or contrast-enhanced mri for whatever reason (i.e., pacemaker) * resection cavity with intraventricular access * significant leakage of radioactivity into csf spaces or ventricles * other actively treated invasive malignancy * breastfeeding women * past medical history of diseases with poor prognosis, e.g., severe coronary heart disease, heart failure (nyha iii/iv), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke, severe mental retardation, pre-existing neurological diseases except those related to glioblastoma or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator) * any active infection (at the discretion of the investigator) * previous participation in a registered clinical trial with therapeutic intervention less than 6 weeks prior to enrolment (date of informed consent) * allergy against known constituents of study medication

Keywords: carbonic anhydrase xii (ca xii) intracavitary radioimmunotherapy fab fragment 6a10